PROJECT SUMMARY The overall goal of the Moffitt Cancer Center (MCC) Chemical Biology and Molecular Medicine (CBMM) Program is to integrate chemical biology and systems biology technologies to develop new therapeutic approaches for the treatment of cancer. The CBMM Program evolved through a strategic merging of the prior Experimental Therapeutics (ET) Program and the drug discovery activities of the Molecular Oncology and Drug Discovery (MODD) Program. This addressed an overlap noted at the prior review and the change was endorsed by MCC's EAC and the NCI. The realignment allows for focused activity in specific areas of excellence within CBMM and better aligns members with focused aims. Along with research in chemistry and drug discovery and clinical trials, the CBMM now includes members interrogating signaling pathways that regulate cell proliferation and survival to identify new targets for cancer therapeutics. Inclusion of basic scientists, chemists, and clinical researchers creates unique opportunities to rapidly translate novel strategies into the clinic, while conversely also increasing the flow of observations from the clinic back to the laboratory for mechanistic testing. To better capture cancer signaling events and opportunities for drug discovery, a major area of growth within CBMM has been target discovery using system-level unbiased mass spectrometry-based proteomics. This strategy has successfully defined mechanisms of acquired resistance in refractory cancers as well as new therapeutic strategies for treating patients. Further, drug discovery science has evolved to enable design of not only single but also dual-targeting small molecule therapeutics using novel chemical probes, solving drug-target structures with x-ray crystallography and structure-based drug design. Tumor profiling technologies, including genomics, proteomics, and imaging, are being fully used for targeted agent clinical trials, defining small molecule mechanisms of action, refining prognostic and predictive markers, and studying the process of drug resistance. As a consequence of these changes, CBMM membership has been consolidated from 57 (30 Scientific, 27 Clinical Trialists) to 43 members (21 Scientific, 22 Clinical Trialists) including 10 new basic science and 15 clinical investigators. CBMM has been successful in obtaining $17.9M in total annual funding, including $10.8M in industry-supported clinical trials, $6.0M in NCI funding, and $0.9M in other peer-reviewed funding. During the current funding period, members published 915 articles, with 318 (35%) of these publications representing intra-programmatic collaborations, 320 (35%) inter-programmatic, and 334 (37%) representing inter-institutional publications with other NCI-designated Cancer Centers. The Program accrued 3,995 patients to interventional clinical trials, including 3,897 to treatment intervention trials.